Lens Epithelium Derived Growth Factor/p75 (LEDGF/p75, or PSIP1) is a transcriptional co-activator that tethers other proteins to gene bodies. The chromatin tethering function of LEDGF/p75 is hijacked by HIV integrase to ensure viral integration at sites of active transcription. LEDGF/p75 is also important for the development of Mixed Lineage Leukemia (MLL), where it tethers the MLL1 fusion-complex at aberrant MLL targets to induce malignant transformation. In addition, LEDGF/p75 might be implicated in the Rett and MECP2 duplication syndromes (neurodevelopmental disorders). Here, we present the structural validation of the LEDGF/p75 binding interactions and targeting strategies for the LEDGF/p75 linked pathologies.